1. Field of the Invention
The present invention is directed to the field of bioartificial pancreases, bioartificial implants generally, and methods for their manufacture and use. In particular, the present invention is directed to the fabrication of thin sheets which enclose cells, which are completely biocompatible over extended periods of time and which do not induce fibrosis. The present invention also concerns cell-containing thin sheets which are easily completely retrievable, and which have dimensions allowing maintenance of optimal tissue viability through rapid diffusion of nutrients and oxygen and also allowing rapid changes in the secretion rate of insulin and/or other bioactive agents in response to changing physiology. The present invention also concerns implantations made using these bioartificial implants. The present invention may be used for implantation of living cells, tissue, drugs, medicines and/or enzymes, contained in the bioartificial implants.
2. Discussion of the Background
Traditional medical treatments for functional deficiencies of biological organs have focused on replacing identified normal secreted products of the deficient organ with natural or synthetic pharmaceutical compositions. For example, for treating insulin-dependent diabetes mellitus (IDDM), also known as type I or juvenile diabetes, the normal secretion of insulin by the islets of Langerhans of the pancreas must be replaced since functional islets are no longer present in the pancreas. This islet function is emulated by administering insulin, titrating the injections in response to blood glucose level measurements. The normal production of hormone by the islets is poorly approximated. This therapy is known to be associated with premature morbidity and mortality.
Organ replacement has also been applied. For IDDM, whole pancreas and islet transplants both have been performed with significant success.sup.1. Such transplants require continuous use of immunosuppressive agents to prevent immunological rejection of the organ, depriving the patient of the full protective function of the immune system against disease and subjecting the patient to the side effects of the drugs.
The bioartificial implant is the manufactured solution to replacing organ function without reliance on immune suppression; this topic has been reviewed.sup.2,3,4,5,6. Many approaches have been tried for fabrication of bioartificial implants having in common the use of some semipermeable barrier allowing the tissue to function and simultaneously protecting tissue from rejection. Prior to the present invention, such bioartificial implants have proven unsatisfactory for a variety of reasons.
Because of severe limits on availability of human tissue, a practical therapy for IDDM will likely require the use of xenografts, most likely of porcine tissue. Porcine tissue is known to stimulate a vigorous immune response in humans, including complement mediated rejection of the xenograft, posing a significant obstacle to use of porcine tissue in a bioartificial implant. The bioartificial implant barrier should sufficiently exclude antibody-complement to prevent complement mediated damage to cell and tissue xenografts.
Some bioartificial implants require grafting into the vascular system, usually with connections to an artery and a vein to take advantage of the pressure difference. Blood flow through such vascular grafts has proven to be traumatic to blood, and continuous systemic administration of pharmaceutical preparations to prevent clotting and foreign body reactions is required. Thus optimal bioartificial implant design, not requiring continuous systemic pharmaceutical administration, is limited to implants that rely on passive diffusion.
Most such passive diffusion bioartificial implants fail because their dimensions are such that the enclosed tissues cannot receive enough nutrients, especially oxygen. When tissue is starved of oxygen its metabolism declines and it loses its ability to secrete hormone. Extended hypoxia leads to cell death.
In these same devices, the tissue may be prevented from responding in a timely way to changes in the physiological environment because of the dimensions of the bioartificial implant. In the case of implants containing insulin-producing islets, an unsatisfactory bioartificial implant may not be able to sense that previously secreted insulin has successfully reduced blood sugar levels, and thus, will continue to secrete insulin even when the effect of this insulin is to plunge blood sugar levels below normal, endangering the host.
Many bioartificial implants fail because their surface is not biocompatible. When exposed to living tissues, especially when they have been seeded with allogeneic or xenogeneic living tissue, they provoke a foreign body response. The foreign body response may be caused by a material on the surface of the implant, antigens shed by the cells within, or by a combination of both. The foreign body response includes fibrosis, in which fibroblasts and macrophages apply proteins including collagen to the surface of the implant, attracting other effector cells, and eventually leading to the formation of a capsule of connective tissue that isolates and starves the implant.
Some bioartificial implants are unsatisfactory because they cannot be easily removed in the event of implant failure or dysfunction.
Some processes previously developed for fabrication of bioartificial implants did not yield reproducible products having the desired porosity and thickness required for the implant.
Some processes previously developed did not completely cover the living tissue, thus allowing access by host immune system to the living tissue, leading to foreign body reactions and/or sensitization and antibody formation followed by complement-mediated lysis.
Some processes previously developed for bioartificial pancreas implants did not make efficient use of islets, wasting a significant fraction of them during fabrication.
Some bioartificial implants are so bulky that implantation is difficult or impossible. This problem occurs when only a small fraction of the volume of the implant consists of living cells.
Prior to the present invention, all bioartificial implants have proven unsatisfactory for one or more of these reasons, and for other reasons as well.